Lactate Dehydrogenase-A (LDH-A) Preserves Cancer Stemness and Recruitment of Tumor-Associated Macrophages to Promote Breast Cancer Progression.

Shengnan Wang,Ziyuan Wang,Chong Chen,Huilin Chen,Zhaojun Duan,Tsung-Hsien Chuang,Qin Si,Huiwen He,Yunping Luo,Lingyu Ma,Yuyang Li

doi:10.3389/fonc.2021.654452

Abstract

Increasing evidence reveals that breast cancer stem cells (BCSCs) subtypes with distinct properties are regulated by their abnormal metabolic changes; however, the specific molecular mechanism and its relationship with tumor microenvironment (TME) are not clear. In this study, we explored the mechanism of lactate dehydrogenase A (LDHA), a crucial glycolytic enzyme, in maintaining cancer stemness and BCSCs plasticity, and promoting the interaction of BCSCs with tumor associated macrophages (TAMs). Firstly, the expression of LDHA in breast cancer tissues was much higher than that in adjacent tissues and correlated with the clinical progression and prognosis of breast cancer patients based on The Cancer Genome Atlas (TCGA) data set. Moreover, the orthotopic tumor growth and pulmonary metastasis were remarkable inhibited in mice inoculated with 4T1-shLdha cells. Secondly, the properties of cancer stemness were significantly suppressed in MDA-MB-231-shLDHA or A549-shLDHA cancer cells, including the decrease of ALDH+ cells proportion, the repression of sphere formation and cellular migration, and the reduction of stemness genes (SOX2, OCT4, and NANOG) expression. However, the proportion of ALDH+ cells (epithelial-like BCSCs, E-BCSCs) was increased and the proportion of CD44+ CD24− cells (mesenchyme-like BCSCs, M-BCSCs) was decreased after LDHA silencing, suggesting a regulatory role of LDHA in E-BCSCs/M-BCSCs transformation in mouse breast cancer cells. Thirdly, the expression of epithelial marker E-cadherin, proved to interact with LDHA, was obviously increased in LDHA-silencing cancer cells. The recruitment of TAMs and the secretion of CCL2 were dramatically reduced after LDHA was knocked down in vitro and in vivo. Taken together, LDHA mediates a vicious cycle of mutual promotion between BCSCs plasticity and TAMs infiltration, which may provide an effective treatment strategy by targeting LDHA for breast cancer patients.

Highlights

Breast cancer stem cells (BCSCs), a small population of tumor cells with self-renewal ability and differentiation potential, have been proposed as a driving force in breast cancer initiation and dissemination [1, 2]
To investigate the role of Lactate dehydrogenase A (LDHA) in breast cancer progression, we analyzed the correlation of LDHA expression with the tumor clinical stages, metastasis, and survival according to TCGA database
The results showed that LDHA expression was markedly increased in patients at tumor advanced-stage or in metastatic tumors (Figure 1A), and high expression of LDHA was significantly associated with short overall survival of breast cancer patients (Figure 1B, P < 0.0001)

Summary

Introduction

Breast cancer stem cells (BCSCs), a small population of tumor cells with self-renewal ability and differentiation potential, have been proposed as a driving force in breast cancer initiation and dissemination [1, 2]. Cancer cells exhibit high glycolysis even in the presence of sufficient oxygen, which is known as Warburg effect [6]. This abnormal metabolism promotes proliferation and survival of tumor cells with elevated glucose uptake and lactate production, and agents targeting glycolysis may offer a therapeutic opportunity in clinical practice [7,8,9]. Intensive studies documenting that elevated LDHA has been associated with the progression of aggressive cancers in a variety of tumor types and different responses to LDHA targeted therapy are shown in clinical settings [12,13,14]. LDHA is indicated to have an essential role in survival and proliferation of tumor cells, relatively little is known about the mechanisms of it on regulating stemness and BCSCs heterogeneity

Methods

Results

Conclusion